PRIMARY INTRACRANIAL GERM CELL TUMORS: Clinicopathologic Review of 32 Cases

Primary intracranial germ cell neoplasms are rare tumors and constitute a heterogeneous group. We have reviewed 32 cases, over a 21-year period, from the University of Florida. The cases include 22 germinomas, 6 mixed germ cell tumors, and 4 teratomas. The clinical presentations in these cases were more closely related to the location of the tumor, that is, pineal or suprasellar, rather than the histologic subtype. Neuroimaging evaluation was useful in distinguishing between germinomas, teratomas, and other mixed germ cell tumors (MGCTs), primarily by evaluation of cystic versus solid lesions (teratoma versus germinoma), contents of cysts (teratoma versus MGCT), and infiltrative nature of the tumors (MGCT), although cytologic-histopathologic confirmation remains necessary. Germinomas responded favorably to radiation therapy with survival periods of over 16 years; MGCTs were treated with combination chemotherapy and radiation, with a markedly poorer prognosis. This study underlines the critical significance of histopathologic evaluation of the tumor in determining therapeutic interventions as well as prognosis.     

Permanent low-activity iodine-125 implants for cerebral metastases

Beginning in 1987, selected patients with metastatic braintumors were treated with permanent implants of low-activityradioactive iodine-125 (¹²⁵I) seeds. These patients underwent craniotomy,gross total resection of the metastatic lesion, andplacement of the seeds. In general, criteria fortreatment included the presence of a recurrent tumorwith a volume too large to permit radiosurgery,and a Karnofsky Performance Score of 70 orhigher. Thirteen patients underwent 14 implant procedures; allreceived external whole-brain radiotherapy. Implant dose ranged from43 Gy to 132 Gy, with a meanof 83 Gy. Survival after implantation ranged from2 weeks to almost 9 years, with amedian of 9 months. Clinical and radiographic localcontrol was obtained in 9 patients. Two patientsdied of acute, postoperative complications within a monthof implantation, so no information regarding tumor controlis available for them. Late complications included abone flap infection in one patient and aCSF leak in another; both were treated withoutfurther sequelae.These results demonstrate that permanent ¹²⁵I implants canresult in good survival and quality of life,and occasionally can yield long-term survival. Potentially, itis a cost-effective treatment in that a separateprocedure for stereotactic implantation or radiosurgery is notneeded, as is the case with the useof temporary high-activity seeds. The permanent implantation itselfadds less than 10 minutes to the craniotomy,and the risk of symptomatic radiation necrosis islow. We recommend consideration of this procedure inpatients harboring large, recurrent metastatic tumors that requirefurther surgery.     

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997     

Assessment of proliferating cell nuclear antigen immunostaining in parotid tumors

We evaluated the prognostic value of immunostaining proliferating cell nuclear antigen (PCNA) by using a monoclonal antibody (PC10) in patients with parotid tumors. Twenty-seven cases were studied. Immunohistochemical studies were carried out on paraffin-embedded tissues from the patients, and the PCNA index was calculated as the percentage of positively staining tumor cells. The PCNA index ranged from 0.1 to 65.3%. We divided the 27 lesions into three groups histologically: group A with benign pleomorphic tumors (11 cases), group B with low-grade malignant tumors (5 cases), and group C with high-grade malignant tumors (11 cases). The mean PCNA index was 0.7% in group A, 2.0% in group B, and 23.1% in group C. The clinical data revealed a significantly higher local tumor recurrence and mortality rate in group C than in groups A and B. We conclude that PCNA may be used as an important indicator for determining clinical prognosis in parotid tumors. Received: 26 July 1997 / Accepted: 28 October 1997     

Facial nerve outcome in lateral skull base surgery for benign lesions

Objective: To statistically identify factors most important in affecting CN7 outcome in lateral skull base surgery for benign lesions. Study Design: A retrospective review of 217 nonmalignancy lateral skull base procedures from 1970 to 1995 at the Otology Group in Nashville. Methods: Charts were reviewed for epidemiology, histopathology, staging, type of CN7 mobilization (none, short, long, severance with reanastomosis, and resection), preoperative and postoperative CN7 function, surgery performed, and survival. Results: Average House-Brackman (HB) scores for mobilizations were as follows: short, 1.65: long, 2.74: and grafting, 4.33. Factors found to affect outcome in a statistically significant fashion were preoperative HB score, staging, type of CN7 manipulation, and surgical approach. Meningiomas were found to have a worse outcome than glomus tumors. Conclusions: Complete resection of tumors should be performed with minimal manipulation of the facial nerve based on regional anatomy and tumor anatomy. Laryngoscope, 108:1480–1484, 1998     

Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid

Vinflunine, or 20′,20′-difluoro-3′,4′-dihydrovino‐relbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20′ position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129–186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated. Received: 13 July 1997 / Accepted: 21 October 1997     

Open MRI-Guided Microsurgery of Intracranial Tumours. Preliminary Experience Using a Vertical Open MRI-Scanner

Summary ? Objectives. A number of different image-guided surgical techniques have been developed during the past decade. None of these methods can provide the surgeon with information about the dynamic changes that occur intra-operatively. The development of open configurated MRI-scanners leads to new perspectives in the intra-operative management and resection control of intracranial tumours.  Material and Method. Using a vertical open 0.5 T MRI-scanner for intra-operative MR image guided neurosurgery, forty-four patients (20 female/24 male) with different intracranial tumours have been operated on since August 1997. The patients ranged in age from 20 to 70 years (mean±standard deviation=47.2±15.9 ys).  Results. In 36 (82%) of 44 patients the tumours were completely removed with the aid of MR image-guidance. In 8 cases (18%) complete removal was not achieved. Postoperatively 6 (14%) of 44 patients developed neurological deficits which were transient in 5 cases (paresis, dysphasia). In these patients the tumours were located in or near eloquent brain areas (sensorimotor cortex/speech center).  Conclusion. Intra-operative MRI is helpful for navigation as well as determining of tumour margins to achieve a complete and safe resection of intracranial lesions. Complications related to the surgical procedure are reduced and the risk of neurological deterioration due to tumour removal and postoperative complications is minimized. It can be concluded that the intra-operative application of interventional MRI technology may represent a major step foreward in the field of neurosurgery.     

Exostoses of the external auditory canal: a long‐term follow‐up study of surgical treatment

To determine the postoperative incidence, extent and recurrence rate of exostoses of the external auditory canal in a cohort of patients involved in different water sports. A cross‐sectional study of 31 patients (46 ears), with exostoses treated by surgery in the Royal Cornwall Hospital between 1980 and 1999. A questionnaire was used to obtain information about the type of water exposure pre‐ and postoperatively. The extent of recurrent stenosis was assessed. The mean postoperative time interval was 10 years (sd = 4.5 years). The degree of stenosis was assessed as: minimal (<30%) in 42.6%, moderate (30–60%) in 31% and severe (>60%) in 25% of ears. The Cox regression model was used to identify factors associated with a reduction in the recurrence rate of stenosis. The use of ear plugs was highly significant (P = 0.015), as was the age of the patient at the time of operation (P = 0.004), i.e. the older the patient, the faster recurrent disease developed. There was no evidence to show that either the type or seasonal pattern of water sport activity influenced recurrence of the disease postoperatively, although preoperatively, the stenosis was more marked in association with surfing and sailing. Exostoses developed faster preoperatively in those who were in the water all year round rather than just the summer months. Of five patients who stopped water sport activity completely after surgery, four of them developed significant recurrent exostoses (>50% stenosis).     

Mammary gland morphology in Sprague-Dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein.

In a related reproductive toxicology study designed to investigate the effects of in utero exposure to environmental toxicants and potential interaction with postnatal genistein, gross enlargement of thoracic mammary glands was observed in female offspring at 200 days of age. Therefore, the objective of this study was to analyze the effect of in utero exposure to a mixture of toxicants on mammary gland morphology. Time-mated Sprague-Dawley rats were treated on days 9-16 of gestation with vehicle or a mixture of environmental toxicants at 1x the acceptable daily intake. Furthermore, it is unclear whether postnatal exposure to phytoestrogens in soy formulas poses breast cancer benefit or risk, and potential interactions with environmental toxicants are unknown. Therefore, half the female pups from each treatment group received either subcutaneous vehicle or genistein (10 microg/g body weight [bw]/day) on postnatal days 2-8. Following necropsy at 200 days of age, a pathologist, blinded to treatment groups, examined mammary gland histopathology. Only mild histological changes were found in mammary glands of rats exposed to the mixture in utero while pronounced ductal hyperplasia, lactational changes, and fibrosis were observed in mammary glands from the genistein group and were more prominent in the mixture + genistein group. Mammary glands of the control group were histologically normal. Collectively, our results reveal that postnatal exposure to pharmacological levels of genistein induces profound morphological changes in the mammary glands of adult female rats, and that high levels of phytoestrogens possess the potential to modulate the toxicological effects of toxicant mixtures.